Derivatives of 3-(2-aminoalkyl)-5-indolol and process therefor



Unit a? atent 3,037,031 Patented May 29, 1962 This invention relates toa new and novel method of preparing compounds of the formula:

onhcnnnn where R is methyl or ethyl and in particular to maleate saltsof said compounds. The method of this invention is adapted to thepreparation of 3-(2aminopropyl)-5- indolol and3-(2-aminobutyl)-5-indolol, also known as a-methyland a-ethyl serotonin,respectively.

Serotonin, that is 3-(2-aminoethyl)-5-indolol or 5- hydroxytryptamine,is known to occur in the body, and is known to influence the functioningof the central nervous, the gastrointestinal and the cardiovascularsystems. It is also known that serotonin is readily oxidized within thebody by the enzyme monoamineoxidase and it has been observed that theblood level of serotonin in a subject increases after the administrationof monoamineoxidase inhibitors. Monoamineoxidase inhibitors such as,B-phenethyl hydrazine have been subject to con siderable investigationin recent years, in view of their aaility to stimulate the centralnervous system and thereby alleviate certain forms of mental depression.

Since serotonin is unstable in the body in the presence of the enzymemonoamineoxidase, administration of serotonin to a subject is noteffective in influencing body functions.

It has, however, been observed that a-methyl and aethyl serotonins arenot attacked by monoamineoxidase with the result that these compoundsrepresent forms of serotonin which are stable in the body. Thus, the 0:-methyl and a-ethyl substituted serotonins remain intact afteradministration and accordingly are effective in treating mentaldisturbances associated with malfunctioning of the central nervoussystem.

Clinical studies on tit-methyl and a-ethyl serotonins have been hamperedheretofore because these compounds have not been available insufliciently pure form for administration to patients. Attempts topurify these compounds by crystallization have met with failure and nopharmaceutically acceptable crystallizable salts of these compounds haveheretofore been known.

It is, accordingly, a particular object of this invention to providea-methyl and ct-ethyl serotonin as pharaceutically acceptable salts inpure form.

It is another object of the present invention to provide a method forthe production of a-rnethyl and aethyl serotonins.

Other objects and the advantages of the invention will become apparentfrom the following detailed description.

It has now been found that a-methyl and a-ethyl serotonins may beprepared by reacting p-benzyloxyphenylhydrazine hydrochloride with anitroaliphatic aldehyde of the formula:

.oughly mixed with the Where R is methyl or ethyl to form a hydrazone ofthe converting the hydrazone to a substituted indole of the formula:

and finally simultaneously reducing the benzyloxy side chain to ahydroxyl group and the nitro group to an amino group to form the desireda-methyl or a-cthyl serotonin, depending upon the particular Rsubstituent present in the nitroaliphatic aldehyde.

It has also been found that the crude a-methyl or ocethyl serotonincontained in the reaction mixture after the reduction may be separatedtherefrom as maleate salts which may be crystallized to obtain a-methylor w ethyl serotonin maleates in pure form. These maleate salts ofot-methyl and a-ethyl serotonins are pharmaceutically acceptable saltsand their discovery permits the administration of oc-methyl and a-ethylserotonins to patients in the treatment and alleviation of certaindepressed conditions of the central nervous system.

The initial step in the reaction sequence of the present inventioninvolves the following reaction:

Mentzer et al., Bull. Soc. Chm. France 24, 421 (1953).

The nitroaliphatic aldehyde may be prepared by the procedure of Shechteret a1. J.A.C.S. 74, 3664 (1952). In the initial development of thereaction scheme of this invention it was found thatp-benzyloxyphenylhydrazine was so unstable that its conversion to thedesired hydrazone appeared to be impossible. It was then found that thehydrochloride derivative of the substituted hydrazine is a stablecompound. However, this presented the further problem in thatp-benzyloxyphenylhydrazine hydrochloride is insoluble in thenitroaliphatic aldehyde. It was finally discovered that an aqueoussolution of a lower alkyl carboxylic acid is a suitable solvent for thereaction. Such carboxylic acids as formic, acetic, propionic and butyricacids at a concentration of about 40 to about percent by weight in waterare useful solvents. It has been found that 50 percent by weight aqueousacetic acid is a particularly effective solvent.

In carrying out the reaction the p-benzyloxyphenylhydrazinehydrochloride is dissolved in a large volume of the solvent by heatingto a temperature in the range of about 30 to about 70 C. This solutionis then thornitroaliphatic aldehyde in the proportions of about 1 mol ofaldehyde per mol of the substituted hydrazine hydrochloride and themixture is allowed to stand overnight. The oil which forms in thereaction mixture is purified by extraction with a suitable solvent suchas chloroform and the solvent is evaporated to yield a dark red oilwhich constitutes the desired hydrazone.

The second step in the reaction sequence of this invention involves theconversion of the hydrazone obtained in the first step to a substitutedindole derivative in the presence of concentrated hydrochloric acid, asfollows:

The hydrazone is dissolved in an aromatic solvent such as benzene,toluene, xylene and the like and the resulting solution is stirredvigorously with concentrated hydrochloric acid at room temperature forseveral hours. Under these conditions the long side chain of thehydrazone rearranges to form a substituted indole derivative.

The conversion of a substituted phenyl hydrazone to an indole derivativeis known in the prior art and is generally referred to as the Fischerindole condensation reaction. If one attempts to carry out a Fischerindole condensation on the p-benzyloxyphenylhydrazone of a4-nitro-4-alkyl butanal using such known Fischer indole condensationcatalysts as concentrated sulfuric acid and zinc chloride, it isimpossible to isolate any appreciable amounts of the desired3-(2-alkyl-2-nitroethyl)-5-benzyloxyindole from the reaction mixture.The use of concentrated hydrochloric acid as a catalyst appears to be ofcritical importance in carrying out a Fischer indole condensation of theparticular hydrazone in the reaction sequence of this invention.

At the conclusion of the indole condensation reaction, the aromaticsolvent phase is processed for recovery of the desired indolederivative, for example, by chromatographic means through acid-washedalumina, followed by recrystallization of the product.

The third step of the reaction sequence of the present inventioninvolves the conversion of the 3-(2-alkyl-2-nitroethyl)-5-benzyloxyindole to the desired a-alkyl serotonin, asfollows:

N02 N ml This reaction involves the simultaneous reduction of thebenzyloxy group to a hydroxyl group and the nitro group to an aminogroup. The reaction may conveniently be carried out in a solventsolution by catalytic hydrogenation in the presence of a conventionalhydrogenation catalyst, for example platinum, palladium and the like.Al-

ternately, the reaction may be carried out in the presence of suchconventional reducing agents as the alkali metal borohydrides, thealkali metal aluminum hydrides, the alkali metal alkoxides and the like.The particular reaction conditions are those normally used with suchreagents.

At the conclusion of the reaction the reaction mixture is treated tofree it from catalyst or reducing agent. This treatment is entirelyconventional. For example, when catalytic hydrogenation has beenemployed, the reaction mixture may be filtered to remove residualcatalyst. Where the reaction has been carried out with chemical reducingagents, the reaction mixture may be treated with water to decompose anyfree reducing agents remaining. The resulting solution may then beprocessed to recover the a-alkyl serotonin therefrom.

It is a particular feature of this invention that a-methyl or oc-Ctl'lYlserotonins may be purified by formation of the maleate salts thereofsince it has been found that maleate salts are crystallizable. They havethe further advantage of representing pharmaceutically acceptable formsof these compounds which may be administered to patients in treatment.

In the initial work on the purification of a-methyl and methylserotonins it was believed that these compounds could be purified byrecrystallization in the form of the same salts as used to purifyserotonin. Serotonin is conventionally purified by crystallization asthe creatinine sulfate salt. However, due to the unique solubilitybehavior of the creatinine sulfate salts of a-methyl and orethylserotonins, it was discovered that these salts could not be purified bycrystallization, the reason being that creatinine sulfate itself is lesssoluble than the creatinine sulfate salts of (at-methyl and a-ethylserotonins and therefore crystallizes from the solution first.

These a-alkyl serotonins can be isolated and purified as thecorresponding picrate salts, but a picrate salt does not represent apharmaceutically acceptable form of compound for administration topatients. Attempts to purify u-alkyl serotonins in the form of saltswith such pharmaceutically acceptable acids as tartaric acid and citricacid proved unsuccessful. It was finally discovered that oralkylserotonins can be crystallized and purified to a high degree as saltswith maleic acid. Accordingly pure uethyl and oc-methyl serotoninmaleates represent the first available pharmaceutically acceptable formsof a-ethyl and a-methyl serotonins for administration to patients.

The novel salts of a-methyl and a-ethyl serotonins of this invention maybe combined with a conventional pharmaceutical carrier to form tablets,capsules, elixirs, solutions or suspensions for injection, suppositoriesand the like suitable for administration to patients.

The following example describing the preparation of a-methyl serotoninmaleate is included in order further to illustrate the method of thepresent invention:

EXAMPLE (a) P-Benzyloxyphelzyllzydrazone of 4-Nifropentanal A quantityof 16.65 gms. (0.0664 mol) of p-benzyloxyphenylhydrazine hydrochlorideis dissolved in 1435 ml. of 50 percent by weight aqueous acetic acid ata temperature of 50 C. 8.7 gms. (0.0664 mol) of 4-nitropentanal is addedto the warm solution, the mixture is shaken until homogeneous andallowed to stand overnight. The insoluble reddish colored oil whichforms is extracted with three 250 ml. portions of chloroform. Thecombined chloroform extracts are washed three times with 150 ml.portions of water and twice with ml. portions of saturated aqueoussodium bicarbonate solution. The washed extract is dried over magnesiumsulfate for one hour and then heated under vacuum to evaporate thechloroform to yield 17.66 grams of a dark red oil which constitutes thep-benzyloxyphenylhydrazone of 4-nitropentanal.

(b) 3-(2-Nitropr0pyl) -5-Benzyl0xyind0le A quantity of 19.04 grams(0.0582 mol) of the pbenzyloxyphenylhydrazone of 4-nitropentanalprepared by the method described in (a) above is dissolved in 188 ml.benzene and 314 ml. 12 N HCl is added. The resulting mixture is stirredvigorously for 6 hours at room temperature. The mixture is filteredthrough a medium porosity sintered glass funnel. The acid layer isremoved and extracted twice with 100 ml. portions of henzene. Thesebenzene extracts are combined with the benzene layer of the filteredreaction mixture. The resulting benzene solution is washed with 80 ml.Water, then with 80 ml, of 5 percent by weight aqueous sodiumbicarbonate solution and finally dried over anhydrous magnesium sulfate.

The dried benzene solution is concentrated under vacuum to a volume of100 ml. and chromatographed through 250 gms. of acid-washed alumina. Theeluate from the column is collected immediately following the dark brownband which proceeds down the column. Benzene is continuously added atthe top of the column until the solids content of the eluate becomesnegligible. The eluate is then evaporated to dryness under vacuum toyield 9.1 gms. of crude 3-(2-nitropropyl)-5-benzy1oxyindole.Recrystallization of the crude product from 40 ml. methanol yields 5.65gms. of pure product. M.P.=8183 C. Calculated elemental analysis for3-(2-nitropropyl)-5-benzyloxyindolc, C18H18N2O3:

Percent: -69.66 H-5.85 N9.03 Found: 0-69.69 H-6.04 N9.22

(c) 3-(2-Amin0p'ropyl) --Ind0l0l; a-M ethyl Serotonin A quantity of 4.70gms. (0.01515 mol) of the 3-(2- nitropropyl)-5-benzyloxyindole, preparedas described in (b) above, is dissolved in 75 ml. absolute ethanol andreduced at 50 pounds per square inch hydrogen pressure in the presenceof 0.80 gm. of 10 percent palladium on charcoal catalyst. At the end of6.5 hours, 97 percent of the theoretical amount of hydrogen has beenabsorbed. The reaction mixture is filtered free of catalyst andevaporated to dryness under vacuum to yield 3.03 gms. of crude3-(2-aminopropyl)-5-indolol or a-methyl serotonin.

(d) a-Methyl Serotonin Maleate The crude u-methyl serotonin obtained asdescribed in (0) above is dissolved in ml. methanol at 50 C. A solutionof 2.03 gms. maleic acid in 5 ml. methanol at 50 C. is added. Theresulting mixture is stirred gently at 50 C. for 5 minutes in thepresence of charcoal and then is filtered and the filtrate allowed tocool slowly to 0 C. The crystals are recovered by filtration, washedwith methanol and dried to yield 2.15 gms. of ix-methyl serotoninmaleate, M.P. 186-187 C. Recrystallization from methanol raises themelting point to 186.5-187" C. Calculated elemental analysis fora-m'ethyl serotonin maleate, C11H14N2O.C4H4O4I C-58.8l H-5.92 N-9.15C-58.78 H-6.03 N9.22

Percent Found 6 I claim: 1. A method of preparing a 3-(2-aminoalkyl)-5-indo1o1 of the formula:

wherein R is selected from the group consisting of methyl and ethylwhich comprises dissolving p-benzyloxyphenylhydrazine hydrochrolide inan aqueous solution of a lower alkyl carboxylic acid containing about 40to about percent by weight of said acid, adding to the resultingsoltuion and mixing therewith an aldehyde of the formula:

RCH-CHz-OH2CHO NO: separating from the reaction mixture a hydrazone ofthe dissolving said hydrazone in an inert aromatic solvent, stirringsaid hydrazone solution with concentrated hydrochloric acid to form a3-(2-nitroalkyl)-5-benzyloxyindole of the formula:

the resulting 3-(2-nitropropyl)-5-benzyloxyindole from the organic phaseand hydrogenating said 3-(2-nitropropyl)-5-benzyloxyindole in thepresence of a palladium on charcoal catalyst to form said3-(2-aminopropyl)-5- indolol.

References Cited in the file of this patent UNITED STATES PATENTS2,708,197 Specter May 10, 1955 2,855,398 Voegtl Oct. 7, 1958 2,908,691Robinson Oct. 13, 1959 FOREIGN PATENTS 721,171 Great Britain -s Dec, 29,1954 807,877 Great Britain Jan. 21, 1959 OTHER REFERENCES Specter etal.: J. American Chemical Society, vol. 73, pages 5514-5 (1951).

Shaw et al.: J. American Chemical Society, vol. 75, pp. 1877-1880(1953).

Noland et al.: J. American Chemical Society, vol. 76, pp. 3227-28(1954).

1. A METHOD OF PREPARING A 3-(2-AMINOALKYL)-5-INDOLOL OF THE FORMULA: